Download Anatomy and physiology of the esophageal body

Diseases of the Esophagus (2012) 25, 292–298
DOI: 10.1111/j.1442-2050.2011.01180.x
Original article
dote_1180
292..298
Anatomy and physiology of the esophageal body
E. Yazaki, D. Sifrim
Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
SUMMARY. The primary role of the esophagus is to propel swallowed food or fluid into the stomach and to
prevent or clear gastroesophageal reflux. This function is achieved by an organized pattern that involves a sensory
pathway, neural reflexes, and a motor response that includes esophageal tone, peristalsis, and shortening. The
motor function of the esophagus is controlled by highly complex voluntary and involuntary mechanisms. There are
three different functional areas in the esophagus: the upper esophageal sphincter, the esophageal body, and the
LES. This article focused on anatomy and physiology of the esophageal body.
KEY WORDS: anatomy, esophagus, physiology.
ANATOMY
The esophagus is a tubular organ with approximately
18–26 cm of length in adults. The esophageal wall is
composed of the mucosa, submucosa, and muscularis
propria. In contrast to in other parts of the gastrointestinal tract, the esophagus does not have
serosal covering, and the outer wall is bounded with a
thin layer of connective tissue. The mucosa of the
esophageal body is made of stratified squamous epithelium, composed of three sublayers: mucous membrane, lamina propria, and muscularis mucosae.
Esophageal submucosa contains glands (esophageal
submucosal glands), although numbers are fewer
than that observed in the rest of the gut.
The esophageal muscularis propria is composed
of a circular muscle layer that is surrounded by a
longitudinal muscle layer. The proximal esophagus
(cervical esophagus) is composed of striated muscle,
and the distal two third of the esophagus (thoracic
esophagus) contains smooth muscles. The transition
from striated to smooth muscle is gradual and there is
a segment (4–6 cm long) that contains both striated
and smooth muscles. Meyer et al.1 reported that this
mixed zone of muscle fibers was approximately 35%
of the esophageal length. This segment is usually
present around the level of the aortic arch. EsoAddress correspondence to: Dr Etsuro Yazaki, MD, PhD,
Wingate Institute of Neurogastroenterology, 26 Ashfield Street,
London E1 2AJ, UK. Email: [email protected]
292
phageal manometry confirms this anatomical zone by
demonstrating that the amplitude of the contraction
wave reaches a minimum in this region.
The esophagus runs posterior to the right of the
aortic arch at the T4 vertebral level. From the level
of T8 until the diaphragmatic hiatus, the esophagus
lays anteriorly to the aorta. The esophagus then runs
through an opening of the diaphragm that is located
anterior to the opening for the descending aorta.
Under normal anatomy, the esophagus is anchored
to the diaphragm, but the esophagus does not tightly
fill the hiatus because it needs to expand to accommodate luminal contents. With aging or other causes,
the amount of elastic tissue in the phrenoesophageal
membrane gradually declines, increasing its laxity
and resulting in risk for developing hiatal hernia.
The esophagus has parasympathetic and sympathetic innervation. The parasympathetic nerve supply
comes from the nucleus ambiguus and the dorsal
motor nucleus of the vagus (DMN) and provides
motor innervation to the esophageal muscles and
secretomotor innervation to the glands. The sympathetic nerve supply comes from the intermediolateral
cell columns of the T1–T10 spine and regulates contractions of blood vessel (blood supply), esophageal
sphincter tone, relaxation of the muscular wall, and
increase in glandular function.
The motor innervation of the esophagus is principally via the vagus nerves. The striated muscle
part of the esophagus is controlled by lower motor
neurons in the nucleus ambiguous in the brainstem,
© 2011 Copyright the Authors
Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
Anatomy and physiology of the esophagus
i.e. swallowing center. The nerve fibers are of the
somatic type and terminate on motor endplates in the
striated muscle fibers. In the smooth muscle segment,
the nerve fibers originate in the DMN. There are two
distinct types of DMN preganglionic neurons. One
type (short latency fibers), in the caudal part of the
DMN, synapses on postganglionic nitrergic inhibitory neurons in the myenteric (Auerbach’s) plexus,
and the other type (long latency fibers), in the rostral
part of the DMN, synapses on the postganglionic
cholinergic excitatory neurons in the myenteric
plexus.2,3 The ganglia of the submucosal (Meissner’s)
plexus regulate secretion and the contraction of the
muscularis musosae. The significance of a scattered
myenteric plexus in the proximal esophageal striated
muscle remains unclear.4,5
Arterial blood supply to the esophagus is provided
by three sources: branches of the inferior thyroid
artery provide arterial blood supply to the upper
esophageal sphincter (UES) and the cervical esophagus; paired aortic esophageal arteries or terminal
branches of bronchial arteries provide blood supply
to the thoracic esophagus; and the left gastric artery
and a branch of the left phrenic artery provide blood
supply to the LES and the most distal segment of the
esophagus. A continuous intensive network arteries
located in the submucosa connects all the extramural
vessels, which results in the copious blood supply to
the esophagus. Blood from the proximal and distal
esophagus is drained via the azygous system, which in
turn drains directly into the superior vena cava. The
left gastric vein, a branch of the portal vein, receives
venous blood from the mid-esophagus. The submucosal connections of veins between the portal and
systemic venous systems in the distal esophagus can
form esophageal varices with portal hypertension.
PHYSIOLOGY
Esophageal secretion
The esophageal submucosa contains glands,
although there are fewer numbers of glands than in
the rest of the gastrointestinal tracts. The esophageal
submucosal glands secrete the following substances:
water, bicarbonate, mucins, epidermal growth factor,
and prostaglandins. Secretions of the esophageal
submucosal glands are involved in mucosal clearance
along with peristalsis and salivary secretion. The
most important secreted substance is bicarbonate,
which plays a protective role during gastroesophageal
reflux.6 This is more significant when non-salivary
source of bicarbonate is required to neutralize
luminal acid, e.g. during sleeping.7
Sensory physiology
Vagal afferents merging from the esophageal smooth
muscle layer and serosa are sensitive to muscle
293
stretch, whereas vagal afferents in the mucosa are
sensitive to various stimuli including chemical (acid),
thermal (cold or hot), and mechanical intraluminal
stimuli.8
In general, vagal afferents do not play a direct role
in visceral pain transmission to the brainstem, but
spinal afferents, which have their cell bodies in the
dorsal root ganglia, are predominantly acting as
nociceptors.8 Spinal afferents terminate in the dorsal
column nuclei (gracilia and cuneatus nuclei) and
project stimuli to the brain through the spinoreticular, spinomesencephalic, spinohypothalamic, and
spinothalamic tracts.9,10
Esophageal pain is known to resemble one from
cardiac origin, i.e. noncardiac chest pain. This resemblance is due to convergence of sensory afferent fibers
from the heart and esophagus in the same spinal
dorsal horn neuron in the cervical and thoracic spinal
cord.11–13 The concept of visceral hypersensitivity
is now well-established in esophageal symptoms.14
Changes in esophageal sensitivity can be caused by
peripheral or central sensitization (neurons in the
spinal cord and brain). Peripheral sensitization has
been reported to be due to upregulation of acidsensing receptors. Acid can activate two proton-gated
ion channels: transient receptor potential vanilloid-1
and acid-sensing ion channels, and activation of these
channels can cause neurogenic inflammation resulting in sensitization of peripheral neurons.15,16 More
recently, dilated intercellular spaces in the basal layer
of the esophageal epithelium have been suggested to
play an important role in peripheral sensitization in
nonerosive reflux disease by favoring increased acid
penetration through the esophageal mucosa.17,18 For
the central sensitization, acid could induce the release
of proinflammatory substances that can sensitize
sensory neurons and would result in the central sensitization.19,20 Another concept, psychoneuroimmune
interactions, has recently been described as one of the
mechanisms for hypersensitivity in nonerosive gastroesophageal reflux disease.14 The mechanisms of
psychoneuroimmune interactions can be explained
by alterations in mucosal permeability, immune activation and pain perception.13,14
Motor physiology
Primary and secondary peristalsis. The coordinated
motor pattern of the esophagus initiated by the act
of swallowing is called primary peristalsis. A rapidly
progressing pharyngeal contraction wave transfers
the bolus through the relaxed UES into the esophageal body, and a progressive circular contraction
begins in the upper esophagus and proceeds distally
along the esophageal body to propel the bolus
through the relaxed LOS. The mean peak pressures
amplitudes are 53 ⫾ 9 mmHg in the proximal esophagus, 35 ⫾ 6 mmHg in the middle, and 70 ⫾ 12 mmHg
© 2011 Copyright the Authors
Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
294
Diseases of the Esophagus
in the distal esophagus.21 The duration of the wave is
normally 2–7 seconds, and the propagation velocity
is 2 to 4 cm/second.21 Primary peristalsis usually
clears most contents of the esophagus into the
stomach, but with ineffective peristalsis, there may be
food residue. Secondary peristalsis is provoked by
residual food or reflux events, and it is not accompanied by pharyngeal contraction or UES relaxation.
The amplitude and velocity of secondary peristaltic
waves are similar to those of primary peristalsis.
Secondary peristalsis in the striated muscle esophagus is regulated by similar central mechanism as
primary peristalsis.22 The control of secondary peristalsis in the smooth muscle part of the esophagus is
a local reflex without demonstrated deglutitive inhibition.23 In secondary peristalsis, mechanoreceptors
in the esophageal wall are excited by distension to
initiate a reflex that may traverse both the extrinsic
and intrinsic nerve pathways. The peripheral reflex
excites an inhibitory innervation, which releases nitric
oxide (NO) to produce inhibition distal to the level
of distension.24
Deglutitive inhibition. Studies using animal models
demonstrated that esophageal smooth muscle was
hyperpolarized before the occurrence of a peristaltic
contraction.25–28 The muscle hyperpolarization lasts
progressively longer in the distal esophageal segments
and is followed by depolarization. Because muscle
contraction is inhibited during hyperpolarization, the
timing of esophageal peristaltic contractions is influenced by the strength and duration of this inhibition.
Because of methodological limitations, electrophysiological measurements of this hyperpolarization in the
esophageal smooth muscle was never demonstrated in
humans, although this was suggested by the phenomenon called ‘deglutitive inhibition’ where swallowing
inhibits ongoing muscular activity in the esophagus.3,29,30 During multiple rapid swallowing (MRS),
the esophageal muscle activity is inhibited, and only
the last swallow is associated with a powerful rebound,
peristaltic sequence known as the after MRS contraction. Sifrim et al.31 reported the first direct evidence
that deglutition produces in the human esophagus a
wave of inhibition that precedes the primary peristaltic contraction. In this study, a balloon placed in
the esophagus was inflated at various positions, and
esophageal motor responses to swallows were studied.
They reported that the duration of swallow-induced
fall in pressure (inhibition) at 13 cm from the LES is
shorter than that at 8 cm (Fig. 1). This study showed
that the latency period before the onset of the peristalsis was a period of inhibition and that there was a
gradient of increasing duration of deglutitive inhibition distally along the human esophagus.
Control of esophageal peristalsis. Peristalsis in the
striated muscle part of the esophagus is entirely
Fig. 1 Sifrim et al. demonstrated the first direct evidence of
a deglutitive inhibition in the human esophagus. A balloon
placed in the esophagus was inflated at various positions, and
esophageal motor responses to swallows were studied. The
duration of swallow-induced fall in pressure (inhibition) at
13 cm from the LES is shorter than that at 8 cm.
dependent on central vagal pathways. It is mediated
by sequential excitation of lower motor neurons
originated in the nucleus ambiguus through the vagus
nerve (Fig. 2).32,33
Control of peristalsis in the smooth muscle part of
the esophagus is more complicated. Peristalsis in the
thoracic esophagus is mediated by both central and
peripheral mechanisms. In contrast to the striated
muscle portion, sequential excitation of vagal efferent
fibers is not essential to exhibit peristaltic waves.3,34
The timing of peristalsis in the smooth muscle
segment is based on the duration of the deglutitive
inhibition that increases distally along the esophagus
1
Nucleus Ambiggus
2
3
UES
1
2
3
Vagus
Striated muscle
Smooth
muscle
part
Fig. 2 Peristalsis in the striated muscle part of the esophagus is
entirely dependent on central vagal pathways. It is mediated by
sequential excitation of lower motor neurons originated in the
nucleus ambiguus through the vagus nerve.
© 2011 Copyright the Authors
Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
Anatomy and physiology of the esophagus
(the latency gradient) followed by deglutitive
rebound excitation.35,36 Weisbrodt and Christensen37
first reported that a latency gradient along the
esophagus was due to noncholinergic inhibitory
nerves in the esophageal wall. Crist et al.2 reported
that the influence of noncholinergic nerve is minimal
at the proximal esophagus and increasing distally and
the cholinergic influence is maximal in the proximal
esophagus and decreasing distally. These studies suggested that that preprogrammed intramural mechanisms, composed of inhibitory (noncholinergic) and
excitatory (cholinergic) neurons, were responsible for
peristalsis in the esophageal smooth muscle together.
A myogenic control system (MCS) is also
reported to regulate esophageal smooth muscle
contractions.38–40 MCS is a fundamental property of
contraction of gastrointestinal smooth muscle.40
There are two important characteristics in MCS:
oscillation of the electrical control activity of the
so-called slow waves and coupling of the smooth
muscle cells in order to work as a functional unit.
A central mechanism also plays an important role
in control of peristalsis in the esophageal smooth
muscle. There are two types of vagal motor fibers that
originate in the DMN: short and long-latency fibers.3
On swallowing, there is near-simultaneous activation
of the short-latency inhibitory vagal fibers that inhibits the entire length of the esophagus.3 This inhibition
is due to a release of NO released from the myenteric
inhibitory neurons.41 There is a delayed and sequential activation of the cholinergic pathway in the longlatency vagal fibers. These cholinergic excitations
only occur after the sequential termination of deglutitive inhibition, and the balance of timing in inhibition
and excitation is the fundamental mechanism that
regulates esophageal peristalsis (Fig. 3).
New insights into esophageal motor physiology based
on observations during high resolution esophageal
manometry. Kahrilas et al.42 described using simultaneous manometry and videofluoroscopy abnormal
bolus clearance associated with hypotensive peristalsis
in the aortic arch region of the esophagus. Based on
this study, Li et al.43 developed a mathematical model
of the esophageal bolus transport. They hypothesized
that bolus retention in the aortic arch region, i.e.
transition zone (TZ), could be due to ‘mismatch’ of the
upper (striated muscle part) and lower (smooth muscle
part) peristaltic waves. This hypothesis was further
studied by Ghosh et al.,44 who analyzed data obtained
from concurrent 21 lumen manometry and videofluoroscopy. They reported that two separate waves –
above and below the TZ – were a part of normal
esophageal motor physiology. The same group, using
concurrent 36ch high-resolution manometry (HRM)
and digital fluoroscopy, confirmed that impaired
coordination between these two waves was associated
with bolus retention in the TZ.45
295
rDMN
cDMN
Excitation
Inhibition
Inhibition
Inhibition
Smooth muscle Inhibition & contractions
LES
Fig. 3 On swallowing, there is near-simultaneous activation of
the short-latency inhibitory vagal fibers in the caudal dorsal
motor nucleus of the vagus (cDMN) that inhibits the entire
length of the esophagus by releasing nitric oxide from the
myenteric inhibitory neurons. There is a delayed activation of
the cholinergic pathway in the long-latency vagal fibers in the
rostral DMN (rDMN). These cholinergic excitations only occurs
after the sequential termination of deglutitive inhibition.
In 1991, Clouse and Staiano46 first described
esophageal pressure topography using conventional
manometry and noted different segmental contractions (S1–S3). Details of these segmental contractions
have been described further with HRM.47,48 The S1
segment originates from the UES and involves the
striated muscle esophagus. S2 and S3 segments
involve smooth muscle esophagus and are predominantly controlled by excitatory (cholinergic) and
inhibitory (NO) neurons, respectively.2,35 Pandolfino
et al.48 recently reported the concept of the contractile
deceleration point (CDP) as an important physiological landmark on esophageal pressure topography.
Using combined HRM and videofluoroscopy, they
found that the CDP of esophageal contractile front
velocity did not occur at the border between S2 and
S3 as previously thought,49 but CDP occurred within
S3 and was indicative of the transition from peristaltic bolus transport to onset of emptying of the
phrenic ampulla. The concept of CDP reflects the
progression of ampullary emptying and can help to
better understand bolus transport across the esophagogastric junction.
Apart from the aforementioned physiological
observations, based on the HRM, a new classification
of esophageal motility disorders has been described (Chicago Classification),47,50 providing a new
approach to esophageal motor physiology and
pathophysiology. Using the HRM, normal esophageal peristalsis can be defined as >30 mmHg isobaric contour with <3 cm defect, contraction front
© 2011 Copyright the Authors
Journal compilation © 2011, Wiley Periodicals, Inc. and the International Society for Diseases of the Esophagus
296
Diseases of the Esophagus
velocity <8 cm, intrabolus pressure <15 mmHg, and
distal contractile integral (DCI) <5000 mmHg/
second/cm.47,50
Longitudinal muscle contraction – esophageal
shortening. Contraction of the esophageal longitudinal smooth muscle is responsible for shortening of
the esophageal wall during peristalsis.51 Although half
of the esophageal mucularis propria is composed
of longitudinal muscle, its role in human esophageal
physiology and pathophysiology is not completely
understood. This is partly due to technical difficulty in
measuring longitudinal muscle contractions in human
and studies were mainly performed on animal models.52,53 A number of techniques have been reported
to assess longitudinal muscle contractions in vivo.
Radio-opaque markers endoscopically clipped along
the long axis of the esophagus have been used.54,55 This
technique involves X-ray fluoroscopy and is not
suitable for prolonged measurements. Recently, highfrequency intraluminal ultrasound (HFIU) has been
introduced as a valid tool to measure longitudinal
muscle contractions in human.56–58
Longitudinal muscles can play an important role
in motor physiology of the esophagus. Dodds et al.59
suggested that both the longitudinal and circular
esophageal muscular contractions were vital to
achieve efficient peristaltic transport of a bolus
through the esophagus. Pouderoux et al.54 reported
that both circular and longitudinal muscle contractions occurred during peristalsis, and the longitudinal
muscle contractions led circular muscle contractions.
Mittal et al.57 suggested that synchrony between
circular and longitudinal muscle contractions was
important as the synchrony created maximal increase
in esophageal muscle thickness, and therefore, circular muscles could efficiently exhibit peak pressure
contractility. Esophageal shortening is also very
important to produce lower esophageal sphincter
axial movement and opening. This is true during
swallowing and also during gastroesophageal reflux.
A localized distal esophageal shortening has been
reported during transient lower esophageal sphincter
relaxation (TLESR),60,61 and it seems to be critical for
reflux to occur during a TLESR.
Abnormal longitudinal muscle contraction and
shortening may be associated to pathology and symptoms: esophageal acidification is known to induce
contraction of the longitudinal muscle.62,63 Paterson
et al.63 have demonstrated in an opossum’s esophagus
that intraluminal acid activates a reflex pathway
involving mast cell degranulation, activation of
capsaicin-sensitive afferent neurons, and the release
of substance P or a related neurokinin, which evokes
sustained contraction of the esophageal longitudinal
smooth muscle. This reflex could be initiated by
changes in mucosal permeability (dilated intercellular
spaces) induced by mucosal acidification.64 These
results suggest that increased esophageal acid exposure can be a possible cause of exaggerated chronic
longitudinal muscle contraction, leading to formation of hiatus hernia.65
Several studies have demonstrated that the esophageal hypermotility (peristalsis) is poorly correlated
to noncardiac chest pain.66–69 Studies using HFIU
described long-lasting thickening of the esophageal
wall (sustained esophageal contraction) associated with chest pain or heartburn.56,70,71 Longitudinal muscle spasm or shortening can therefore be an
important mechanism for esophageal symptoms.
Esophageal body tone. Based on in vitro studies and
manometric studies in vivo, it has been traditionally
believed that the esophageal body has no resting tone.
In 1993, Mayrand and Diamant72 first demonstrated
using a modified barostat that active tone was indeed
present in the smooth muscle esophagus, and compliance and resting tone differed between the smooth
and striated muscle segments of the esophagus. This
finding was confirmed by other investigators reporting the presence of the tonic contractions in the
esophageal body.53,73,74
Little is known about the relevance and neural
modulation of esophageal tone. Zhang et al.75 demonstrated that tonic contractile activity was strongly
modulated by a cholinergic neural excitatory input.
Bilateral vagotomy and atropine provoked more than
50% decrease in esophageal tone. They also suggested
that NO may have a complementary inhibitory role.
Esophageal tone was decreased by sildenafil and
increased by L-NNA.
Esophageal body tone might compensate the negative intrathoracic pressure induced by the respiration.
A tonic esophageal wall might be relevant as a background for the occurrence and organization of
efficient phasic peristaltic contractions. It has been
reported that changes in esophageal tone might
modulate the proximal extent of gastroesophageal
reflux.76 It is thought that changes in esophageal tone
could be one of the important components in normal
swallowing along with circular muscle contraction
(peristalsis) and contraction of longitudinal muscle
(shortening), although further studies are required
to understand the significance of this low resting tone
in motor physiology of esophagus.
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